Our current focus is to use candidate gene studies to identify molecules that affect the outcome in chronic nerve pain conditions. Identification of such genes would encourage pharmacologists to develop new drug treatments to imitate pain-reducing gene effects. Our primary clinical condition of interest is lumbar root pain from herniated intervertebral disc. This is one of the most costly chronic pain conditions in the US population. It is ideal for candidate gene studies because the anatomy and clinical presentation of disc herniation is so uniform, and it is common enough to allow the collection of the large numbers of patients essential to candidate gene studies. Because the physiology of the nerve root is similar in the lumbar spine and in the facial region (trigeminal nerve root) we will use results from the common spinal condition to understand less common orofacial nerve root pain conditions, including idiopathic trigeminal neuralgia (?tic douloureaux?) and traumatic and cancer related trigeminal nerve disorders. We are also carrying out randomized controlled trials of treatments for chronic lumbar nerve root pain, and providing our genetics expertise to other research groups who study other kinds of pain disorders and mood disorders.[unreadable] [unreadable] Our most important result was to show that a common variant that reduces function of the GCH1 gene appears to protect against pain in patients undergoing lumbar spine surgery for sciatica, and in normal humans given experimental pain stimuli (Tegeder et al., Nature Medicine, in press.) In these studies, we collaborated with the Woolf lab at Harvard, which identified a critical role of this gene in rats with three types of nerve injuries, and with investigators at the University of Florida and North Carolina dental schools. The Harvard group is beginning to explore the feasibility of developing drugs to reduce the function of this gene, to mimic the pain resistance found in people with this variant. We also examined the variability of the amount of depression and anxiety felt by patients after a successful or unsuccessful spine operation for back and leg pain. We illustrated an original method to analyze the effects of genetic variants on these mood changes (Max et al., Molecular Pain, online). We speculate that genetic differences explain some of the differences in patients responses to pain, and that such studies could help to identify new antidepressant or antianxiety treatments for patients with chronic pain.[unreadable] [unreadable] Because temporomandibular joint area pain (TMD) is an important orofacial condition, we offered our genetics expertise to William Maixner?s group at the University of North Carolina Dental School, who had done a longitudinal study of normal young women to determine the risk factors for developing TMD. Last year?s Human Molecular Genetics paper (Diatchenko et al, 2005) reported a study in which 200 normal young woment were tested for sensitivity to 16 laboratory pain tests, and genotyped for polymorphisms of the COMT gene. We identified three genetic variants (haplotypes) of COMT that the Maixner group found to confer levels of pain sensitivity they called low pain sensitive (LPS), average pain sensitive (APS), and high pain sensitive (HPS). These variants account for 11% of variability in experimental pain perception. This was the first study that has identified a genetic polymorphism associated with the risk of developing a chronic pain condition, and helped these investigators obtain funding for a definitive study of 3200 subjects. In the current year, we participated in publications that described the effects of the COMT haplotypes on responses to each of the 16 experimental pain tests (Diatchenko et al., Pain, in press, 2006) and that examined the more subtle effects of variants in the beta-2 adrenergic receptor (Diatchenko, Am J Med Genet, 2006).[unreadable] [unreadable] Our group?s other genetics publications this year included the description of the effects of variants in the genes for galanin (Belfer et al., Molecular Psychiatry) and its galanin-3-receptor (Belfer et al., Genes, Brain, and Behavior) on the risk of alcoholism in Finns and Native American tribes, and the effects of an alpha-2C adrenergic receptor polymorphism on brain responses to emotional stimuli in depressed patients (Neumeister et al., Neuropsychopharmacology). [unreadable] [unreadable] Our group also completed several clinical trials in patients with chronic pain. In one of these studies, Khoromi et al. (J Pain) showed that the anticonvulsant drug, topiramate, reduced chronic nerve root pain by about 18% compared to placebo in the 29 patients who completed a two period crossover study. This is the first report of any drug being helpful in this type of pain over a period of several months. However, the usefulness of the drug is lessened by frequent side effects such as sleepiness and change in taste. A clinical trial of magnetic belt treatment of chronic nerve root pain also showed an average pain reduction of 18% compared to a control treatment, but this was not statistically significant (Khoromi et al., J Pain Symptom Management, in press). Another study showed that chronic pain did not affect the levels of sex and adrenal hormone secretion in males with osteoarthritis pain (Khoromi et. al., J Clin Endocrin Metab). If pain patients develop hormonal abnormalities, other causes must therefore be sought..[unreadable] [unreadable] We also coauthored a paper on the methods of analyzing and presenting clinical trial results (Farrar et al., J Pain Symptom Management), examination of predictors of response to opioids in patients with postherpetic neuralgia (Edwards et al., Anesthesiology), five review articles or chapters on methods of pain research and treatment, and a chapter on pain genetics.